Crystal structure

ABSTRACT

A process for the production of crystals with controlled surface smoothness, size, shape and degree of crystallinity, compositions comprising such crystals, and the use of certain crystals, especially lactose, lactose monohydrate, fluticasone propionate, salmeterol xinafoate, salbutamol sulphate or ipratropium bromide in pharmaceutical compositions.

The present invention relates to an improved process for producingcrystals with controlled surface smoothness, size, shape and degree ofcrystallinity. It also relates to compositions comprising such crystalsand to the use of certain crystals to produce improved pharmaceuticalcompositions.

US5254330 discloses the fact that decreasing the rugosity of carrierparticles facilitates redispersion of drug particles from compositionscomprising carrier particles. The document describes a process forpreparing particulate sugar crystals (preferred carrier particles). Theprocess involves crystallisation from a saturated aqueous solution bythe addition of at least an equal volume of a water immiscible organicsolvent and a quantity of a solvent which is miscible with both waterand the organic solvent. The solvent mixtures are preferably brisklyagitated throughout the period of crystallisation and crystal growth.However, the carrier particles described in this document are ofvariable size (5 to 1000 micrometers).

Constant stirring is essential for the crystallisation of a substancefrom solution so as to avoid caking and the formation of othernon-dispersible aggregates. However, mechanical stirring is likely tointroduce random energy fluctuations in the solution, causingheterogeneous distributions of local concentrations. Such a hypothesisis supported by the phenomenon that a supersaturated solution can beinduced to nucleate by a mere tap on the side of the vessel. Thefluctuations in local concentrations induced by mechanical stirring mayresult in the heterogeneous growth of crystals since the growth rate islargely dependent upon the supersaturation of its surrounding solution.The heterogeneous growth will thus lead to the production of crystalswith different particle size and irregular shapes, both of which havebeen commonly encountered when crystallisation is carried out underagitation. Further, mechanical stirring is known to induce secondarynucleation, which takes place in the presence of existing crystals(Larson, Chem. Eng. Commun, 1981, 12; 161). Thus, if a crystal isgrowing in a suspension under constant agitation, then, additionalnuclei will continually be added to the crystal size distribution. Sincethe nucleation step also depletes the available supersaturation, indirect competition with the growth of the nuclei, the newly borncrystals will grow to a lesser degree than the previously existentcrystals. This will further widen the particle size distribution offinal crystals. Therefore, mechanical stirring almost always results inthe production of crystals with a wide size distribution with a largeportion of small crystals and this can be seen from the particle sizedistribution of lactose prepared under constant stirring (Valle-Vega andNickerson, J. Food Sci., 1977; 42; 1069-1072). Such a size distributionshould be avoided in the preparation of lactose particles intended to beused as the carrier particles for inhalation aerosols since the majorityof the particles are required to have a size range of 63-90 μm. Thecrystal shape is primarily determined by the supersaturation of theenvironment from which the crystals have been grown. Differences insupersaturation can be expected to result in the production of lactosecrystals of different shape and surface textures. Crystals with suchmorphological properties would have inconsistent performance when usedas carrier particles for any adhered drug particles.

Mechanical stirring (or agitation) also induces collisions betweenexisting crystals, crystals and the wall of the vessel, and between thecrystals and any agitation devices. The collision energy may cause smallpieces of the crystals to be chipped away, which will then bedistributed subsequently within the suspension. The chipped parts ofcrystals may act as stable embryos for new crystals to grow. Any chippedsites on the surface of broken crystals may also act as nuclei for newcrystals to grow. Even if new crystals do not grow out of any chippedsites of a larger crystal, these fracture planes will undergo irregulargrowth, increasing the irregularity of both particle shape and surfacetextures of the affected crystal. Therefore, it may be advantageous toeffect crystallisation from an undisturbed system, without any means ofagitation, with a view to producing crystals with well definedmorphology.

In order to grow crystals in an undisturbed system without the formationof any non-dispersible aggregates, crystals have previously beensuspended in a gel (Mullin, in Crystallisation (Third edition)Butterworth-Heinemann Ltd., Oxford, 1993). The gel provides a protectivebarrier for the growing crystals and permits a steady diffusion ofcrystallising molecules. Without introducing any external turbulence tothe solution, the gel can be expected to provide a homogeneousenvironment in which the crystals can grow and thus, overcome some ofthe major problems associated with the use of mechanical stirring. Sincethe crystals are in a stagnant suspension, individual crystals grow andmature without any fractures. Crystals prepared in this manner alwayshave a more regular shape and a smoother surface than those obtainedunder mechanical stirring. Therefore, crystallisation from a gel hasbeen widely used to obtain large, single crystals with well definedmorphology. Further, secondary nucleation will occur to a much lesserextent in a gel than in the case of the solution under agitation. Theinhibition of such nucleation may result in a narrower size distributionof the final particles. Monocrystals of α-lactose monohydrate have beengrown in a 0.7% w/w agar gel (Wong and Aulton, J. Pharm. Pharmacol.,1987; 39 (suppl.); 124P). However, the use of an agar gel may not proveto be suitable for the preparation of lactose particles intended to beused as a carrier for inhalation devices since agar is not apharmaceutical excipient, and harvesting the bulk of crystals from anagar gel would prove to be problematic due to the relatively highconsistency of the gel. Agar is also insoluble in most of the commonorganic solvents and this would make it very difficult to remove anyadsorbed agar gel from the crystal surface.

Therefore, there is a need for a process which allows crystals to growwithout any means of agitation during the crystallisation, and whichprovides large quantifies of crystals.

Surprisingly, we have now found a process which allows crystals to beprepared without mechanical stirring or agitation during the period ofcrystallisation and crystal growth. The crystals so produced overcomethe disadvantages of large variations in size and shape, and haveimproved surface smoothness and degree of crystallinity, and have anelongated shape. There are many fields in which such crystals would beof particular advantage, for example carrier and drug particles for usein inhaled pharmaceutical formulations, and for additives in paints.

The present invention provides a crystallisation process, said processcomprising:

-   a) dissolving the substance to be crystallised in a medium wherein    the viscosity of the medium can be adjusted;-   b) applying a means for adjusting the viscosity of the medium until    a gel with an apparent viscosity in the range 25 to 90 Pa.s at a    shear rate of 1 s⁻¹ is reached;-   c) allowing crystal growth;-   d) applying a means for adjusting the viscosity of the medium until    a fluid with an apparent viscosity less than 25 Pa.s at a shear rate    of 1 s⁻¹ is reached; and-   e) harvesting the crystals.

The means for adjusting the viscosity of the medium may be, for exampletemperature change ultrasound, thixotropicity, electro-rheology(application of an electric current), mechanical shear chemical additive(for example, sodium chloride or ethanol), or pH change. Preferably, themeans for adjusting the viscosity of the medium is pH change.

The medium may be in the form of an aqueous or organic solution of apolymer. Preferably, the medium is an aqueous solution of a polymer.

The substance to be crystallised may be a drug substance, a chemicalintermediate, an excipient, for example a carrier for drug particlessuitable for use in an inhaled pharmaceutical composition, or may be,for example an additive for paint. Preferably, the substance to becrystallised is a water-soluble drug or a pharmaceutically acceptablecarrier.

The crystals may be harvested by standard techniques known in the art.For example, the crystals may be collected by filtration, centrifugationor by decanting the supernatant and drying the crystals. Preferably, theharvested crystals are washed in a solvent in which the medium issoluble and the crystals are insoluble.

Numerous medicaments, especially those for the treatment of respiratoryconditions such as asthma, are administered by inhalation. Since thedrug acts directly on the target organ much smaller quantities of theactive ingredient may be used, thereby minimising any potential sideeffects caused as a result of systemic absorption. The efficacy of thisroute of administration has been limited by the problems encountered inmaking appropriate and consistent dosages available to the lungs. Thedelivery systems currently available are pressurised metered doseinhalers, nebulisers and dry powder inhalers.

Metered dose inhalers require good co-ordination of actuation andinhalation in order to achieve consistent dose administration; thisco-ordination may be difficult for some patients. Nebulisers areeffective but are relatively expensive and bulky and as a result aremainly used in hospitals. A variety of dry powder inhalers have beendeveloped and, since dry powder inhalers rely on the inspiratory effectof the patient to produce a fine cloud of drug particles, theco-ordination problems associated with the use of metered dose inhalersdo not apply.

It has been found that medicaments for administration by inhalationshould be of a controlled particle size in order to achieve maximumpenetration into the lungs, preferably in the range of 1 to 10micrometers in diameter. Unfortunately, powders in this particle sizerange, for example micronised powders, have a high bulk volume and havevery poor flow characteristics due to the cohesive forces between theindividual particles. These characteristics create handling and meteringdifficulties during manufacture of the medicament powder and, mostimportantly, adversely affect the accurate dispensing of the powderwithin the inhalation device. A number of proposals have been made inthe literature to improve the fluidity of dry powder pharmaceuticalformulations.

GB1520248 describes the preparation of soft pellets of finely powderedsodium cromoglycate which have satisfactory fluidity within thereservoir of the inhaler device but have sufficiently low internalcoherence to break up into finer particles of medicament when introducedinto the turbulent air stream in the mouthpiece of the device. Numerousother published patent applications suggest the use of carriermaterials, for example GB1402423, particularly of coarser carriers withparticles having sizes falling within a given range, for exampleGB1242211, GB1381872, GB1410588, GB1478020 and GB1571629. WO87/05213describes a carrier which comprises a conglomerate of one or more solidwater-soluble diluents and a lubricant, EP0260241 describes alipid-based dry powder composition, and U.S. Pat. No. 5,143,126describes a method of preparing flowable grain agglomerations offormoterol and lactose. Unfortunately the selection of the particle sizeof the drug and excipient and of the ratio of drug to excipientinevitably involves a compromise between adequate bulk and flowproperties for metering and the desired redispersability of fineparticle drug in the inhaled air flow.

Surprisingly, the process of the present invention can be used toproduce crystals of drug or carrier with controlled size and shape,improved surface smoothness and degree of crystallinity, and anelongated shape. Such crystals overcome some of the formulationdifficulties of compositions for inhalation.

In one preferred embodiment, the present invention provides acrystallisation process, said process comprising:

-   a) dissolving the substance to be crystallised in an aqueous    solution of a medium wherein the viscosity of the medium is    pH-dependent;-   b) adjusting the pH of the medium until a gel with an apparent    viscosity in the range 25 to 90 Pa.s at a shear rate of 1 s⁻¹ is    reached;-   c) allowing crystal growth;-   d) adjusting the pH of the medium until a fluid with an apparent    viscosity less than 25 Pa.s at a shear rate of is 1 s⁻¹ reached; and-   e) harvesting the crystals.

Preferably the substance to be crystallised is a material suitable foruse as a carrier or a drug in dry powder inhaler compositions. Preferredcarriers include mono-saccharides, such as mannitol, arabinose, xylitoland dextrose and monohydrates thereof, disaccharides, such as lactose,maltose and sucrose, and polysaccharides such as starches, dextrins ordextrans. More preferred carriers comprise particulate crystallinesugars such as glucose, fructose, mannitol, sucrose and lactose.Especially preferred carriers are lactose and lactose monohydrate.

Preferably the average size of the particles of the carrier whendistributed by mass is in the range 5 to 1000 micrometers, morepreferably in the range of 50 to 250 micrometers, and most preferably inthe range 50 to 100 micrometers. Typically at least 95% of the particleswill be of a size which falls within this range.

Preferred drugs which may be administered in the powder compositionsaccording to the invention, and which may also be crystallised accordingthe present invention, include any drugs usefully delivered byinhalation for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;anti-infectives, e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines or pentamidine; antihistamines, e.g.methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide,budesonide, tipredane, triamcinolone acetonide or fluticasone;antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine,adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,salbutamol, salmeterol, terbutalin; isoetharine, tulobuterol,orciprenaline or(-)-4-amino-3,5-dichloro-α[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics, e.g. ipratropium, atropineor oxitropiurn; hormones, e.g. cortisone, hydrocortisone orprednisolone; xanthines, e.g. aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g. insulin or glucagon. It will be clear to a person skilledin the art that, were appropriate, the drugs may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimise the activity and/or stability of the drug.

Particularly preferred drugs for administration using powdercompositions in accordance with the invention include anti-allergics,bronchodilators and anti-inflammatory steroids of use in the treatmentof respiratory disorders such as asthma by inhalation therapy, forexample cromoglycate (e.g. as the sodium salt), salbutamol (e.g. as thefree base or as the sulphate salt), salmeterol (e.g. as the xinafoatesalt), terbutaline (e.g. as the sulphate salt), reproterol (e.g. as thehydrochloride salt), beclomethasone dipropionate (e.g. as themonohydrate), fluticasone propionate or(-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol.Salmeterol, salbutamol, fluticasone propionate, beclomethasonedipropionate and physiologically acceptable salts and solvates thereofare especially preferred. Most preferred are fluticasone propionate,salmeterol xinafoate, salbutamol sulphate and ipratropium bromide.

Preferably the medium used to prepare the crystals intended to be usedas a carrier in dry powder inhalation formulations will meet at leastthe following criteria. First, the medium should be suitable for use asa pharmaceutical ingredient for internal usage. Second, the mediumshould preferably be capable of being efficiently removed from thesurface of the crystals so as not to affect any physico-chemicalproperties of the crystals and, most importantly, to minimise thepossibility of introducing such a compound to the respiratory tract.Third, the consistency or viscosity of the medium can be controlled suchthat after crystallisation, the bulk of crystals can be harvested easilywithout any vigorous treatment that might change the morphology of thecrystals.

Preferably the polymer which comprises the medium is a Carbomer.Carbomers, a group of polyacrylic acid polymers cross-linked with eitherallylsucrose or allyl ethers of pentaerythritol, provide a medium thatmeets the aforementioned criteria. Carbomers have been widely used assuspending agents; emulsifying agents or tablet binders inpharmaceutical industry. Carbomer gels have also been employed asbioadhesive vehicles for mucoadhesive drug delivery formulations toprolong drug residence at the application sites. The viscosity ofCarbomer gels is known to be dependent upon the polymer concentration(Barry and Meyer, Int. J. Pharm. 1979; 2; 1-25) and therefore, it ispossible to obtain a minimal viscosity that can suspend the crystalswithout substantially inhibiting crystal growth. The viscosity ofCarbomer gel changes reversibly with the pH value of the solution (Barryand Meyer, Int. J. Pharm, 1979; 2; 2740). Carbomers disperse in water toform acidic colloidal solutions of low viscosity which, whenneutralised, produce highly viscous gels. The viscosity reaches amaximum at pH 6-11 but is considerably reduced if the pH is less than 3or greater than 12. Therefore, the crystallisation can be carried out ina neutralised Carbomer gel. After which, the gel can be converted to afluid by acidification such that the crystals may be readily harvested.In order to remove medium from the surface of the crystals, a solvent inwhich a Carbomer is soluble but the crystals are insoluble is required.Carbomers are soluble in both ethanol and glycerine, whereas thepreferred crystals, lactose, are insoluble in these solvents. Therefore,any adsorbed Carbomer residue on lactose crystals may be easily removedby washing the crystals with either ethanol or glycerine withoutsubstantially changing the morphology of the crystals.

The pH of the medium may be adjusted by the addition of an aqueous base,for example it may be raised by the addition of aqueous sodium hydroxidesolution, or it may be lowered by the addition of an aqueous acid, forexample it may be lowered by the addition of hydrochloric acid.

Most preferably the medium is a Carbopol 934™ gel. Preferably the gel isan aqueous dispersion of Carbopol 934™ at a concentration of at least0.4% w/w. Preferably, the concentration of Carbopol 934™ is in the range0.4-0.8% w/w.

Preferably, the pH of the Carbopol 934™ gel is initially adjusted to bein the range pH 6.5-7.5, providing an apparent viscosity in the range25-90 Pa.s at a shear rate of 1s⁻¹, depending on the concentration.Preferably, the gel has a static yield value in the range 0.14-2.81 Pafor step b) of the process, to prevent crystals in the size range50-1000 μm from sedimentation.

Preferably, after the crystal growth the pH of the Carbopol 934™ gel isadjusted to be in the range pH 3-3.5, providing a fluid. Preferably, thefluid has a static yield value <0.14 Pa.

It will be understood by those skilled in the art that other Carbomersmay be used in the present invention, with concentration and pHparameters determinable by methods known in the art.

Preferably crystal growth is monitored, for example by use of an opticalmicroscope, until the majority of the crystals have grown to a size inthe range 50-125)μm, more preferably 63-90)μm.

In one aspect, the present invention provides crystals preparedaccording to the process as hereinbefore described. Preferably, thecrystals are lactose monohydrate crystals.

When the medium is a Carbomer, preferably the harvested crystals arewashed in a solvent in which the Carbomer is soluble and the crystalsare insoluble, for example ethanol or glycerine.

In a further aspect, the present invention provides crystals obtainableby the process as hereinbefore described. Preferably, the crystals arelactose monohydrate crystals.

Crystals, for example lactose monohydrate crystals, prepared accordingto the process of the present invention, have a significantly highermean elongation ratio and “surface factor” (see Table 3), and animproved degree of crystallinity (see Table 4) and flowability(significantly smaller angle of slide, see Table 5) than crystalsprepared by the constant stirring technique.

Accordingly, one aspect of the present invention provides lactosemonohydrate crystals having an elongation ratio of 1.58±0.33 and a sizein the range 63-90 μm.

Surprisingly, we have found that crystals having high elongation ratiosmay, when employed as carrier particles in powder compositions suitablefor inhalation, increase the fine particle fraction (FPF) of themedicament being carried, compared to crystalline carrier particles withlower elongation ratios (see Table 6). Since formulations that produce ahigher FPF can be expected to deliver a higher fraction of medicament tothe lower airways than those which produce a lower FPF, crystals with ahigher elongation ratio provide advantageous formulations when employedas carrier particles.

Accordingly, the present invention provides use of carrier particles,preferably to lactose monohydrate crystals, with an elongation ratio inthe range 1.55-2.20, preferably in the range 1.60-2.10, in themanufacture of powder formulations for inhaled use with improved drugfine particle fractions.

Elongated carrier particles, including crystals prepared according tothe present invention, may be used to form pharmaceutical powdercompositions suitable for inhalation with advantageous properties. Suchcompositions enable improved redispersion of drug particles.

Accordingly, one aspect of the present invention provides apharmaceutical composition comprising elongated carrier particles,preferably elongated lactose monohydrate crystals, preferably in theform of elongated lactose monohydrate crystals prepared according to theprocess of the present invention, and particulate drug. The compositionmay optionally comprise a further pharmaceutically acceptable diluent orcarrier.

Preferably the pharmaceutical composition comprises lactose monohydratecrystals having an elongation ratio in the range of 1.55-2.20,preferably 1.60-2.10.

The pharmaceutical composition may usefully additionally comprise anyparticulate drug suitable for administration by inhalation, such asthose mentioned hereinbefore. It will be appreciated by those skilled inthe art that the compositions according to the invention may, ifdesired, contain a combination of two or more active ingredients. Drugsmay be selected from suitable combinations of the drugs mentionedhereinbefore. Thus, suitable combinations of bronchodilatory agentsinclude ephedrine and theophylline, fenoterol and ipratropium, andisoetharine and phenylephrine formulations.

Other compositions may contain bronchodilators such as salbutamol (e.g.as the free base or as the sulphate salt), salmeterol (e.g. as thexinafoate salt) or isoprenaline in combination with an anti-inflammatorysteroid such as a beclomethasone ester (e.g. the dipropionate) or afluticasone ester (e.g. the propionate) or a bronchodilator incombination with an antiallergic such as cromoglycate (e.g. the sodiumsalt). Combinations of isoprenaline and sodium cromoglycate, salmeteroland fluticasone propionate, or salbutamol and beclomethasonedipropionate are especially preferred.

The final powder composition desirably contains 0.1 to 90% w/w,preferably 0.5 to 75% w/w, especially 1-50% w/w, of drug relative to theweight of the carrier particles.

Once formed, the carrier particles may be admixed with microfineparticles of one or more medicaments, optionally together with one ormore conventional pharmaceutically acceptable ingredients, usingconventional techniques to prepare the powder compositions according tothe invention.

The compositions according to the invention optionally contain one ormore conventional pharmaceutically acceptable ingredients such asdiluents and flavouring agents. The particle size of any suchingredients will preferably be such as to substantially prevent theirinhalation into the bronchial system upon administration of the powdercomposition, desirably in the range of 50 to 1000 micrometers.

The final composition desirably contains 0.1 to 90% w/w, preferably 2 to20% w/w of medicament and 10 to 99.9% w/w, preferably 50 to 99% w/w ofcarrier particles.

The compositions according to the invention may conveniently be filledinto a bulk storage container, such as a multi-dose reservoir, or intounit dose containers such as capsules, cartridges or blister packs,which may be used with an appropriate inhalation device, for example asdescribed in GB2041763, WO91/13646, GB1561835, GB2064336, GB2129691 orGB2246299. Such inhalers which contain a composition according to theinvention are novel and form a further aspect of the invention. Thecompositions of the invention are particularly suitable for use withmulti-dose reservoir-type inhaler devices in which the composition ismetered, e.g. by volume from a bulk powder container into dose-meteringcavities. The lower limit of powder delivery which may be accuratelymetered from a multi-dose reservoir-type inhaler device is in the regionof 100 to 200 micrograms. The formulations of the present invention aretherefore particularly advantageous for highly potent and hence low dosemedicaments which require a high ratio of excipient for use in amulti-dose reservoir-type device.

Dry powder inhalers are designed to deliver a fixed unit dosage ofmedicament per actuation, for example in the range of 10 to 5000micrograms medicament per actuation, preferably 25 to 500 micrograms.

Administration of the compositions of the present invention may beindicated for the treatment of mild, moderate or severe acute or chronicsymptoms or for prophylactic treatment. It will be appreciated that theprecise dose administered will depend on the age and condition of thepatient, the particular medicament used and the frequency ofadministration and will ultimately be at the discretion of the attendantphysician. When combinations of medicament are employed the dose of eachcomponent of the combination will in general be that employed for eachcomponent when used alone. Typically, administration may be one or moretimes, for example from 1 to 8 times per day, giving for example 1, 2, 3or 4 unit doses each time.

Thus, for example, each actuation may deliver 25 micrograms salmeterol,100 micrograms salbutamol, 25, 50, 125 or 250 micrograms fluticasonepropionate or 50, 100, 200 or 250 micrograms beclomethasonedipropionate.

The present invention further provides the use of lactose monohydratecrystals, as hereinbefore defined, in the preparation of apharmaceutical composition.

The present invention is illustrated by the following Examples.

EXAMPLES Example 1

Preparation of Lactose Monohydrate Crystals Using the Constant StirringTechnique

One-step crystallisation from aqueous solution—A predetermined amount oflactose (Lactochem™, Borculo Whey Ltd., Chester, UK) was dissolved in100 ml distilled water at 80° C. After filtration through a Whatmanfilter paper (<0.45μm), the solution was transferred to a 150 ml glassbeaker which had been placed in either an ice bath or a water bath at40° C. The solution was stirred at 500 rpm (Heidolph Overhead Stirrer,Fisons Laboratory Instruments, UK) with a 4 blade (1×3 cm) stirrer whichwas situated 2 cm above the bottom of the container. After thecrystallisation was allowed to continue for a predetermined period oftime, the crystals were filtered and washed sequentially with 60% (v/v)and absolute ethanol, respectively. The crystals were allowed to dry atroom temperature overnight before drying in a vacuum oven at 70° C. for3 h. After a small amount of sample (about 0.5 g) was taken from eachbatch of lactose for the measurement of particle size, shape and surfacesmoothness, the remaining lactose crystals were poured into a 90 μmsieve which had been placed upon a 63 μm sieve. The particles were thensieved manually and slowly for 1 h so as not to rupture any crystals.The particles were divided into 3 size fractions (<63, 63-90 and >90μm), which were collected and weighted separately. The lactose crystalsthus obtained (batches 1 to 11) were transferred to a sealed vial andplaced into a desiccator over silica gel until required for furtherinvestigation. The samples obtained are given in Table 1 below.

Two stage crystallisation from aqueous solution—Lactochem™ lactose (200g) was dissolved in 200 ml distilled water at about 90° C. The solution(about 320 ml) was filtered while still hot through a Whatman filterpaper (0.45 μm). It was then transferred to a 500 ml glass beaker andstirred at 500 rpm with a 4 blade (1×3 cm) stirrer which was situated 2cm above the bottom of the container. Lactose was then allowed tocrystallise under constant stirring at room temperature at 500 rpm for2.5 h. The crystals (A) were filtered and the mother liquor was placedback into the beaker and allowed to crystallise further for 16 h toobtain crystals (B). Batches A and B were washed with 60% (v/v) andabsolute ethanol, respectively, and were allowed to dry at roomtemperature overnight. The lactose crystals were poured into a 90 μmsieve which had been placed upon a 63μm sieve. The particles were thensieved manually and slowly for 1 h so as not to rupture any crystals.Batch (A) was classified into batches 13 and 14, which had a particlesize range from 63-90 μm and <63μm respectively. Batch (B) wasclassified into batches 15 and 16, which had a particle size range from63-90 cm and <63 μm respectively. The crystals were then dried in avacuum oven at 70° C. for 3h. The lactose crystals thus obtained(batches 13 to 16) were transferred to a sealed vial and placed into adesiccator over silica gel until required for further investigation. Thesamples obtained are in Table 1a below.

TABLE 1 Lactose T Time Diameter (d_(w)) ± % Particle (μm) Batch No (%w/w) (° C.) (h) SD (μm) <63 63-90 >90 Shape 1 33 40 12 83.6 ± 12.8 13.945.8 40.3 Tomahawk 2 33 40 24 115.8 ± 14.6  5.6 15.1 79.3 Tomahawk 3 330 24 100.3 ± 18.9  15.2 17.2 67.6 Irregular 4 43 0 5 94.4 ± 13.4 19.621.8 56.6 Irregular 5 43 0 12 104.5 ± 14.8  14.9 23.2 61.9 Irregular 643 40 5 103.8 ± 20.6  14.4 21.6 64.0 Tomahawk 7 33 0 12 63.7 ± 9.4  33.040.0 26.8 Irregular 8 43 40 12 100.6 ± 15.3  24.5 17.9 57.6 Pyramid 9 5040 3 88.8 ± 13.8 27.5 31.9 40.6 Prism 10 60 40 0.3 76.4 ± 15.7 33.8 46.319.9 Elongated 11 60 40 1.5 91.8 ± 17.9 26.3 27.6 46.1 Elongated

TABLE 1a Batch No Diameter (d_(SV)) (μm) 13 104.7 14 68.6 15 93.0 1665.3

Example 2

Preparation of Lactose Monohydrate Crystals Using Carbomer Gel

A predetermined amount of distilled water was agitated at about 500 rpmwith a 4-bladed stirrer (1×3 cm) which was situated 2 cm above thebottom of a 500 ml beaker. The required amount of Carbopol 934™ (B FGoodrich Chemical Co., Cleveland, Ohio, USA) with an average molecularweight of approximately 3,000,000, was added into the vortex. When allthe Carbopol was dispersed, the liquid was allowed to stand overnight inthe dark so as to ensure maximum dissolution of the polymer. A cloudy,colloidal solution of low viscosity was obtained, the pH of which wasabout 3.2. The required amount of Lactochem™ lactose was then dissolvedin the Carbopol solution at an elevated temperature (<90° C., dependingupon the final lactose concentrations) under constant stirring at 500rpm to obtain a cloudy solution with a pH value of approximately 2.5.Sodium hydroxide solution (1 M) was then added dropwise to the solution,whilst stirring at about 800 rpm. The viscosity and clarity of thesolution increased with pH, until it became a clear homogenous gel atapproximately pH 4.5. After then, the mixer was not sufficientlypowerful to disperse the gel and hence, the mixing was continuedmanually with a spatula. The addition of the neutralising agent (NaOH)was continued so as to obtain pH 7. The gel was then centrifuged at 3000rpm for about 10 min so as to remove any entrapped air bubbles andinsoluble particles. The gel was finally placed in the dark until themajority of the crystals had grown to the size range of 63-90 μm, whichwas estimated by an optical microscope, the gel was adjusted to pH 3-3.5with hydrochloric acid (1 M) to obtain a fluid. The crystals wereallowed to settle for about 10 min. After decanting the supernatant, thecrystals were routinely washed with 60% ethanol twice and absoluteethanol three times. The crystals were finally allowed to dry at roomtemperature after which, a small amount of sample (about 0.5 g) wastaken from each batch of lactose, the remaining lactose crystals werepoured into a 90 μm sieve which had been placed upon a 63 μm sieve. Theparticles were then sieved manually and slowly for 1 h so as not torupture any crystals. The particles were thus divided into 3 sizefractions (<63, 63-90 and >90 μm) which were collected and weightedseparately. The classified lactose crystals were dried in a vacuum ovenat 70° C. for 3 h before transferring to sealed vials, which were thenplaced in a desiccator over silica gel.

Crystallisations of the lactose from Carbopol 934™ gels were carried outunder different conditions by means of altering the crystallisation timeand the concentrations of either lactose or Carbopol gels (Table 2).Three batches of lactose crystals were prepared under each of the sevenconditions listed in Table 2 but in each case the 3 batches were thenmixed to prepare final batches of lactose, which were labelled as Car 1to Car 7, respectively. The 63-90 μm fraction of batches Car 1 to Car 7were labelled as C1 to C7, respectively. Lactose crystals from batch Car1 were further classified into fractions <63; 90-125 and >125 μm, whichin turn were labelled as C8; C9 and C10 respectively. Batch C7 waswashed directly with 100% ethanol rather than prewashing with 60% v/vethanol as described above.

The samples obtained are given in Table 2 below:

TABLE 2 Crystal Mean Batch Lactose Carbopol time Size % Particle (μm)No. (% w/v) (% w/v) (h) (μm) <63 63-90 >90 Car 1 43.0 0.6 72 105.4 5.835.4 58.8 Car 2 43.0 0.3 24 87.9 10.3 56.5 33.2 Car 3 33.0 0.3 24 76.512.2 68.7 19.1 Car 4 50.0 0.4 48 116.3 8.2 12.6 79.2 Car 5 50.0 0.6 72114.2 1.4 22.3 76.3 Car 6 38 0.4 72 93.3 8.5 53.5 38.0 Car 7 38 0.4 4875.4 15.6 73.2 11.2

Example 3

The shape factor (Scir), elongation ratio (E) and surface factor (Srec)of the samples was calculated in the following manner:

A small amount of lactose particles was scattered on a microscope slideusing a small brush ensuring that the particles deposited separately.The slide was then mounted on an optical microscope (Labophot-2, Nikon,Japan) and the images of the particles were transferred to an IBMcompatible computer through a Nikon camera. Particle images wereanalysed automatically using analySIS 2.0 (SIS Image Analysis GmbH,Germany) and the following descriptors were employed to quantify themorphology of lactose crystals:${{Shape}\quad{factor}} = {S_{cir} = \frac{4\quad\Pi\quad{area}}{{perimeter}^{2}}}$${{Elongation}\quad{ratio}} = {E = \frac{Length}{Width}}$${{Surface}\quad{factor}} = {S_{rec} = {S_{cir} \times \frac{\left( {1 + E} \right)^{2}}{\Pi\quad E}}}$All the particles that were projected onto the monitor were analysed andmore than 100 particles were measured for each batch.

TABLE 3 Crystallisation with Crystallisation in Constant StirringCarbopol 934 ™ gels Batch Batch No. S_(cir) E S_(rec) No. S_(cir) ES_(rec) 1 0.74 1.39 0.97 C1 0.76 1.58 1.02 2 0.74 1.39 0.97 C2 0.70 1.610.94 3 0.60 1.28 0.78 C3 0.68 1.59 0.91 4 0.68 1.29 0.88 C4 0.73 1.851.02 5 0.72 1.30 0.93 C5 0.76 1.55 1.01 6 0.69 1.64 0.93 C6 0.71 2.031.02 7 0.74 1.34 0.96 C7 0.68 1.78 0.94 8 0.72 1.37 0.94 9 0.78 1.631.05 10 0.68 2.08 0.99 11 0.73 1.71 1.00 13 0.65 1.79 0.90 14 0.65 1.550.87 15 0.69 1.81 0.96 16 0.72 1.54 0.96

Example 4

Degree of Crystallinity

X-ray powder diffraction (XRPD) patterns for different batches oflactose were performed (FIG. 1). All batches had similar XRPD patternsto α-lactose monohydrate (Brittain et al, Pharm. Res. 1991, 8, 963-973and Sebhatu et al, Int. J. Pharm. 1994, 104, 135-144). However,different batches showed different peak intensities, which wereindicative of different degrees of crystallinity of these lactosecrystals.

X-ray powder diffractometry has been widely used to determine the degreeof crystallinity of pharmaceuticals (Suryanarayanan, in Brittain HG(Ed), Physical Characterisation of Pharmaceutical Solids, Marcel Dekker,NY, 1995, 187-222). Some XRPD methods involve the demarcation andmeasurement of the crystalline intensity and amorphous intensity fromthe powder patterns (Nakai et al., Chem. Pharm. Bull. 30, 1982,1811-1818) whilst others employ an internal standard such as lithiumfluoride to measure the crystallinity of drugs. Therefore, it is notpossible to calculate the absolute degree of crystallinity by the XRPDpatterns in FIG. 1 since neither 100% amorphous lactose nor any internalstandard was measured. However, since the degree of crystallinity is afunction of either the integrated intensity (area under the curve) orthe peak intensity (height), the relative degree of crystallinity ofdifferent samples of the same crystal forms may be compared by theirpeak intensity at the same diffraction angle. The relative degree ofcrystallinity (RDC) was defined as the ratio of the peak intensity of agiven sample of a single polymorphic form to that of another specimen ofthe same polymorph which produced the greatest possible response (Ryan,J. Pharm. Sci. 75, 1986, 805-807). RDC may be employed to determine therank order of crystallinity of different batches of lactose crystals.The integrated peak intensities at 2θ=12.5°, 16.5°, 23.8° and 27.5°,which are characteristic for α-lactose monohydrate, were determined bymeasuring the areas under the curve of the X-ray diffraction profiles.The RDC was calculated by dividing the sum of the four integrated peakintensities of each batch by that of batch C7 since this batch producedthe greatest trace of X-ray diffraction. It can be seen from Table 4that the degree of crystallinity decreases in the order of batchC7>batch C1>Lactochem™ lactose>batch 11>batch 14.

TABLE 4 Estimates of the integrated peak intensities (cm²) of XRDPs andthe relative degreee of crystallinity (RDC) of lactose crystals Angle(2θ) Lactochem ™ Batch 11 Batch 14 C1 C7 12.5° 0.72 0.70 0.41 0.58 0.8116.5° 0.11 0.88 0.10 0.67 0.68 23.8° 0.16 0.11 0.16 0.45 0.40 27.5° 0.040.07 0.07 0.19 0.17 Sum 1.03 0.96 0.74 1.89 2.06 RDC (%) 50.0 46.6 35.991.7 100

The lactose crystals prepared from Carbopol 934 ™ gels had a higherdegree of crystallinity than lactose particles crystallised underconditions of constant mechanical agitation.

Example 5

Flowability

The angle of repose (θ_(r)) for batches of lactose crystals was measured(at least in triplicate) by pouring a sample of crystals into a coppertube (2.65 cm×6.90 cm), which had been placed over a flat base with adiameter of 2.53 cm. After the powder heap reached a height ofapproximately 4 cm, the addition of powder was stopped and the coppertube was slowly lifted vertically off the base, on which a cone ofpowder was formed. The height of the cone was measured using a ruler andthe θ_(r) calculated as:$\theta_{r} = {{Tangent}^{- 1}\left( \frac{hp}{r_{b}} \right)}$

-   -   where hp is the height (cm) of the powder heap and rb is the        radius (cm) of the base.

The angle of slide (θ_(s)) for batches of lactose crystals was measured,at least in triplicate, by placing lactose crystals (approximately 10mg) on a stainless steel plane (6.55×7.00 cm). The plane was tilted byscrewing a spindle vertically upwards below the plane. When the majorityof the powder started to slide, the angle between the tilted plane andthe horizontal base, θ_(s), was directly read from a protractor.

The results are listed in Table 5.

TABLE 5 The angle of repose and angle of slide of different batches oflactose crystals [mean (SD), n ≧ 3] Crystallisation with Crystallisationin Constant Stirring Carbopol 934 ™ gels Batch θ_(r) θ_(s) Batch θ_(r)θ_(s) No. (°) (°) No. (°) (°) 1 43 (1) 50 (1) C1 46 (1) 48 (0) 3 41 (1)47 (1) C2 40 (0) 43 (1) 4 43 (1) 50 (2) C3 41 (2) 45 (1) 5 46 (2) C4 40(1) 45 (2) 6 53 (1) 62 (1) C5 42 (2) 48 (1) 7 38 (0) 43 (1) C6 41 (0) 43(1) 8 56 (2) >90 C7 43 (1) 40 (1) 9 37 (1) 43 (1) Lactochem ™ 48 (2) 50(1) 10 34 (1) 38 (1) 11 32 (1) 34 (1) 13 58 (1) 74 (1) 14 60 (0) >90 1557 (2) 71 (0) 16 59 (1) >90Table 5 shows that different batches of lactose exhibited differentdegrees of both the angle of repose (θ_(r)) and the angle of slide(θ_(s)). Lactose particles from batches 10 and 11 produced significantly(p<0.01) smaller values of θ_(r) or θ_(s), than the other batches oflactose, indicating that the former had higher flowability than thelatter. The majority of lactose crystals from batches 10 and 11 had anelongated, cuboidal shape (Table 1). Elongated particles are known tobuild up open packings of high porosity. In flow, such particles tend tobe oriented with their long axes in the direction of the flow and ifsuch an orientation is achieved, these particles show less internalfriction than more isometric particles (Neumann, Adv. in Pharm. Sci. 2,1967, 181-221). Batches 14 and 16 produced the largest θ_(r) and theseparticles did not even slide off the plane that had been tilted to anangle of 90° to the horizontal, indicating that these two batches oflactose were highly cohesive and had poor flowability. This is likely tobe attributable to the smaller mean diameter (approximately 65 μm) ofbatches 14 and 16 in comparison to the other batches of lactose (>90 μm)since powders of smaller particle size are known to produce larger θ_(r)due to their internal cohesiveness (Neumann, Adv. in Pharm. Sci. 2 1967,181-221). Lactose particles prepared from Carbopol 934 gels showed moreconsistent values of θ_(r) (40-46°) and θ_(s) (40-48°) in comparison tocrystals prepared using agitation and this is likely to be due to moreeffective control of their particle morphology. Further, the crystalsprepared from Carbopol 934 gels appeared to have better flowability thanthe majority of the batches prepared under constant stirring since theyhad significantly (p<0.01) smaller values of 0 than the other batches oflactose (batches 1-8). The angle of repose differs from the angle ofslide in that the former is determined by the least stable particleswhilst the latter depends largely on the average conditions for the bulkof the powder (Hiestand, J. Pharm. Sci. 55, 1966, 1325-1344). Therefore,the angle of slide may correlate more closely with flow properties thanthe angle of repose.

Example 6

Deposition Profiles of Salbutamol Sulphate from Different Batches ofLactose Crystals

Salbutamol sulphate and lactose were mixed in a ratio of 1:67.5, w/w inaccordance with the ratio employed in the commercial “Ventolinl™”formulation. After drying in a vacuum over at 40° C. for 12 h,micronised salbutamol sulphate with mass median diameter 2.0 μm (GlaxoWellcome Group Ltd., Ware, UK) (25 mg), was weighed into a 10 mlstoppered sample vial to which had been added one spatula full oflactose crystals. The vial was stoppered and placed on a Whirlymixer for5 s. Then, more lactose particles (similar to the amount of the blend)was added to the vial and the blend was mixed on a Whirlymixer foranother 5 s. This process was repeated until all the lactose (1.750 g)had been incorporated into the salbutamol sulphate/lactose blend toobtain a ratio of drug to carrier of 1 : 67.5, w/w. The stoppered vialswere then placed in a Turbula mixer (Glen Creston Ltd., Middx, UK) andmixed for 30 min. The samples were then stored in a vacuum desiccatorover silica gel until further required.

Ten samples were taken randomly from each batch. The sample(approximately 33 mg) was weighed accurately and the amount ofsalbutamol sulphate was measured by HPLC. The coefficient of variationof the drug content was employed to assess the homogeneity of themixtures.

Hard gelatin capsules (Size 3, Rotacapsule™, Glaxo Wellcome Group Ltd.,Ware, UK) were filled with 33.0±1.5 mg of the powder mixture so thateach capsule contains 481±22 μg salbutamol sulphate, which was the unitdose contained in a Ventolin Rotacap™. The filling was performedmanually.

Ethyl paraben was dissolved in the mobile phase to produce a solutionwith a concentration of 4 μg ml⁻¹.

An accurately weighed amount of salbutamol sulphate (20.0 mg) wastransferred to a 100 ml volumetric flask, dissolved in the internalstandard solution, and made up to volume to obtain a concentration of0.2 mg ml-1 of salbutamol sulphate (solution A). 10.0 ml of solution Awas pipetted into another 100 ml volumetric flask and diluted to volumewith the internal standard solution to obtain a solution containing 20μg ml⁻¹ salbutamol sulphate (solution B).

Aliquots of solution B (0.25, 0.50, 1.00, 2.00, 3.00, 4.00, 5.00, 6.00,7.00 ml) were pipetted into 10 ml volumetric flasks and made up tovolume using the internal standard solution to obtain a series of thestandard solutions which contained drug concentrations of 0.5, 1.0, 2.0,4.0, 6.0, 6.0, 10, 12 and 14 μg ml⁻¹ respectively. These standardsolutions were employed to construct a calibration curve of drugconcentration against the peak area ratios of drug to internal standard.The calibration was prepared on a daily basis and a calibration curvewith r²>0.99 was considered acceptable.

Approximately 33 mg of the powder mixture was accurately weighed anddissolved in the internal standard solution. After the solution had beensonicated in a water bath for 30 min, it was filtered through amillipore filter (Whatman membrane filters, 0.45 μm, nylon, Whatman Lab.Division, Kent, UK). 30 μl of the filtrate was injected into the HPLC.No interference from the lactose carrier was observed. The concentrationof salbutamol sulphate was calculated by interpolation using thepreviously constructed calibration curve.

HPLC mobile phase containing the internal standard (7 ml) was introducedinto the upper stage and 30 ml of the same solvent into the lower stageof a twin stage liquid impinger. The capsule, to be tested, was placedin a commercially available inhaler (either Rotahaler™, Glaxo Wellcome,Ware, UK or Cyclohaler™, Pharbita BV, the Netherlands), which had beenfitted into a moulded rubber mouthpiece attached to the throat piece ofthe impinger. Once the assembly had been checked and found to beairtight and vertical, the vacuum pump was switched on. After the pumphad run for 5 s, the dose was released. the pump was allowed to run foranother 7 s at 60±11 min⁻¹ following the release of the dose and it wasthen switched off. The capsule shells were removed from the inhalerdevice and the deposition test was repeated until six capsules has beenactuated in the same manner. The inhaler body, capsule shells and mouthpiece were washed 5 times with the mobile phase containing internalstandard and the washing solution was made up to 100 ml with the samesolvent. The sample thus obtained was used to measure the amount of drugretained in the inhaler device. The same process was carried out forboth the upper and the lower stage of the twin-impinger. All the samplesobtained were analysed for the concentration of salbutamol sulphateusing HPLC.

The recovered dose (RD) was the sum of the drug collected in the inhalerdevice, upper and lower stages of the impinger, whilst the emitted dose(ED) was the amount of drug released from the inhaler device, i.e. thesum of drug collected at upper and lower stages of the impinger.However, fine particle dose (FPD) was defined as the amount of drugdeposited in the lower stage of the impinger, which has a diameter lessthan the cut-off diameter of the upper stage of a twin-impinger (6.4 μmat an air flow rate of 60±11 min⁻¹). The fine particle fraction (FPF)was calculated as the ratio of the fine particle dose to either therecovered dose (FPF % RD) or the emitted dose (FPF % ED). The totalrecovery (% recovery) of the drug was assessed by the ratio of therecovered dose to the theoretical dose, the latter being the dose ofsalbutamol sulphate in the capsules. For example, the theoretical doseof salbutamol sulphate in one capsule was 481±22 μg, which wasequivalent to the filling weight (33.0±1.5 mg) of lactose and salbutamolsulphate blends.

The mixtures were found to be homogenous with a coefficient of variationin salbutamol sulphate content of less than 2.2% (n=10).

The deposition data in Table 6 were calculated as one capsule peractuation at 60 l min⁻¹ via a Cyclohaler™. It can be seen that therecovered dose (RD) of salbutamol sulphate varied from 391 μg for theblend containing batch 9 lactose to 508 μg for the blend composed ofbatch 10 lactose, corresponding to a % recovery of between 81.2-105.5%.The drug recovery was reasonably satisfactory with an average recoveryof 94.1% from all of the eight formulations investigated. The emissionof drug from the inhaler device ranged from 55.6% for blends containingbatch 9 lactose to 70.8% for blends containing batch 10 lactose, with anaverage drug emission of 66.5%, indicating that a large portion (33.5%RD) of the drug was retained in the inhaler device.

The blends containing batch 9, 10, 11 and Lactochem™ lactose produced asimilar fine particle dose (FPD) of salbutamol sulphate, which wassignificantly higher (p<0.01) than that obtained from the blends whichwere composed of batch 3, 4 or 7 lactose. The blends containing batch 9lactose produced the highest FPF in terms of both % RD (25.6%) and % ED(46.2%), which were more than twice the FPF of the formulationscontaining batch 3 lactose, the FPF of the latter being 12.6% RD or19.8% ED. These batches of lactose particles had similar particle sizebut with different surface smoothness and particle shape. Thedifferences in particle shape and surface texture of lactose carrierparticles may account for the differences in the deposition of the drugsince all the powders are composed of the same batch of salbutamolsulphate. The lowest values for FPF of drug, obtained using blendscontaining batch 3 or 4 lactose may be due to those batches having theroughest surfaces with the least elongated particle shape.

TABLE 6 Deposition of salbutamol sulphate from different batches oflactose in a twin-impinger after aerosolisation at 60 l min⁻¹ via aCyclohaler ™ [mean (SD), n ≧ 3]. Batch RD ED FPD FPF Recovery EmissionNo. (μg) (μg) (μg) % RD % ED % % *Lact 460 (20) 320 (37) 101 (12) 21.8(1.7) 31.6 (3.5) 95.7 (4.2) 69.3 (6.0) 3 432 (18) 276 (15)  54 (10) 12.6(2.4) 19.8 (3.9) 89.7 (3.8) 63.8 (0.9) 4 425 (24) 294 (10) 64 (2) 15.1(0.8) 21.8 (0.7) 88.3 (5.0) 69.1 (1.7) 6 454 (20) 319 (14) 91 (8) 20.0(1.9) 28.5 (1.9) 94.4 (4.1) 70.2 (1.9) 7 398 (28) 257 (34)  69 (18) 17.2(3.3) 26.6 (3.6) 82.7 (5.9) 64.6 (4.0) 9 391 (48) 217 (29) 101 (18) 25.6(1.5) 46.2 (3.8)  81.2 (10.0) 55.6 (2.5) 10  508 (13) 359 (5)  113 (5) 22.3 (1.6) 31.5 (1.9) 105.5 (2.7)  70.8 (0.8) 11  450 (35) 344 (40) 108(7)  21.8 (2.5) 31.9 (5.4) 103.9 (7.3)  68.7 (3.7) *Lact = Lactochem ™lactoseThe surface smoothness and particle elongation have been quantifiedpreviously using the terms “surface factor” and elongation ratio,respectively. FIGS. 2 and 3 show these shape and surface descriptors oflactose carrier particles against the drug FPF of the correspondingblends.

From FIGS. 2 and 3, it can be seen that increasing the surfacesmoothness of lactose carrier particles, as expressed by the “surfacefactor”, generally resulted in an increase in the FPF of salbutamolsulphate in terms of either % RD or % ED. Interestingly, increasing theelongation ratio of the lactose carrier particles also resulted in anincrease in the FPF of salbutamol sulphate (FIG. 3). These resultssuggest that apart from surface smoothness, the elongation of carrierparticles may also play an important role in determining the FPF of thedrug.

1. A crystallisation process for lactose or lactose monohydratecomprising: a) dissolving lactose or lactose monohydrate in an aqueoussolution of a Carbomer; b) applying a means for adjusting the viscosityof the aqueous solution of a Carbomer until a gel with an apparentviscosity in the range 25 to 90 Pa.s at a shear rate of 1 s⁻¹ isreached; c) allowing crystal growth; d) applying a means for adjustingthe viscosity of the aqueous solution of a Carbomer until a fluid withan apparent viscosity less than 25 Pa.s at a shear rate of 1 s⁻¹ isreached; and e) harvesting the crystals.
 2. A crystallisation process asclaimed in claim 1, wherein the means for adjusting the viscosity of theaqueous solution of a Carbomer is temperature change, ultrasound,thixotropicity, electro-rheology, mechanical shear, chemical additive,or pH change.
 3. A crystallisation process as claimed in claim 2,wherein the means for adjusting the viscosity of the aqueous solution ofa Carbomer is pH change.
 4. A crystallisation process as claimed inclaim 1, wherein the crystals are harvested by means of collection byfiltration.
 5. A crystallisation process as claimed in claim 1, whereinthe process comprises: a) dissolving lactose or lactose monohydrate tobe crystallised in an aqueous solution of a Carbomer wherein theviscosity of the medium is pH-dependent; b) adjusting the pH of theaqueous solution of a Carbomer until a gel with an apparent viscosity inthe range 25 to 90 Pa.s at a shear rate of 1 s⁻¹ is reached; c) allowingcrystal growth; d) adjusting the pH of the aqueous solution of aCarbomer until a fluid with an apparent viscosity less than 25 Pa.s at ashear rate of 1 s⁻1 is reached; and e) harvesting the crystals. 6.Lactose monohydrate crystals obtained according to the process asclaimed in claim
 1. 7. A pharmaceutical formulation for administrationby inhalation comprising lactose monohydrate crystals as claimed inclaim
 6. 8. A pharmaceutical formulation for administration byinhalation comprising lactose monohydrate crystals as claimed in claim 6and/or fluticasone propionate or salmeterol xinafoate crystals.
 9. Acrystallisation process as claimed in claim 1, wherein the crystallisedlactose monohydrate has an elongation ratio of 1.58±0.33 and a size inthe range of 63 to 90 μm.
 10. A lactose monohydrate according to claim6, having an elongation ration of 1.58±0.33 and a size in the range of63 to 90 μm.
 11. Lactose monohydrate according to claim 6, having anelongation ratio from 1.55-2.20.